A diminished visual acuity or total loss of vision may result from a number of eye diseases or disorders caused by dysfunction of tissues or structures in the anterior segment of the eye and/or posterior segment of the eye. To understand why human vision declines with age, much research has focused on the retina, the layer of rod and cone photoreceptors cells that convert light into electrical signals. Studies in mice have shown that age-related decreases in retinal rod cell function cannot be explained by rod cell loss, abnormal retinal plasticity or any signs of retinal disease (Jackson, G. R., Owsley, C. & McGwin, G., Jr. Vision research 39, 3975-3982 (1999); Gao, H. & Hollyfield, J. G. Investigative ophthalmology & visual science 33, 1-17 (1992); Jackson, G. R., Owsley, C., Cordle, E. P. & Finley, C. D. Vision research 38, 3655-3662 (1998)). Indeed, Jackson and colleagues reported a dramatic slowing of rod-mediated dark adaptation after light exposure associated with human aging that was related to delayed regeneration of rhodopsin (Jackson, G. R., Owsley, C. & McGwin, G., Jr. Vision research 39, 3975-3982 (1999)).
Age related macular degeneration (AMD) is one of the specific diseases associated with the posterior portion of the eyeball and is the leading cause of blindness among older people. AMD results in damage to the macula, a small circular area in the center of the retina. Because the macula is the area which enables one to discern small details and to read or drive, its deterioration may bring about diminished visual acuity and even blindness. The retina contains two forms of light receiving cells, rods and cones, that change light into electrical signals. The brain then converts these signals into the images. The macula is rich in cone cells, which provides central vision. People with AMD suffer deterioration of central vision but usually retain peripheral sight.
Inadequate availability and/or processing of vitamin A to the visual chromophore, 11-cis-retinal, can adversely affect vertebrate rhodopsin regeneration and visual transduction (reviewed in McBee, J. K., Palczewski, K., Baehr, W. & Pepperberg, D. R. Prog Retin Eye Res 20, 469-529 (2001); Lamb, T. D. & Pugh, E. N., Jr. Prog Retin Eye Res 23, 307-380 (2004); and Travis, G. H., Golczak, M., Moise, A. R. & Palczewski, K. Annu Rev Pharmacol Toxicol (2006). As in aging, rhodopsin regeneration after light exposure is more delayed in humans and mice deprived of vitamin A due to either dietary deficiency or inadequate intestinal absorption (Lamb, T. D. & Pugh, E. N., Jr. Prog Retin Eye Res 23, 307-380 (2004)). Moreover, treatment with vitamin A and its derivatives may have beneficial effects in aging (Jacobson, S. G., et al. Nat Genet 11, 27-32 (1995)) and retinal diseases such as Sorbsby's fundus dystrophy (Jacobson, S. G., et al. Nat Genet 11, 27-32 (1995)) and retinitis pigmentosa (Berson, E. L., et al. Arch Ophthalmol 111, 761-772 (1993)).
Retinoid absorption, storage and recycling after bleaching of retinal pigments is impaired in mice lacking lecithin:retinol acyltransferase (LRAT) (i, Y., Batten, M. L., Piston, D. W., Baehr, W. & Palczewski, K. J Cell Biol 164, 373-383 (2004); Batten, M. L., et al. PLoS medicine 2, e333 (2005); Batten, M. L., et al. J Biol Chem 279, 10422-10432 (2004); O'Byrne, S. M., et al. J Biol Chem 280, 35647-35657 (2005)) and a null mutation in the human LRAT gene results in early-onset rod-cone dystrophy (Thompson, D. A., et al. Nat Genet 28, 123-124 (2001)). The latter resembles a form of human Leber's congenital amaurosis (LCA) in which disabling mutations in the retinal pigment epithelium-specific 65 kDa (RPE65) gene also cause severe rod and cone photoreceptor dysfunction (Thompson, D. A., et al. Nat Genet 28, 123-124 (2001)). LCA patients carrying mutations in both the LRAT and RPE65 genes may, like Lrat−/− and Rpe65−/− knockout mice, lack 11-cis-retinal and rhodopsin, possess abnormalities in all-trans-retinyl ester levels within RPE cells, show severe impairment of rod and cone photoreceptor functions and exhibit retinal degeneration (Imanishi, Y., Batten, M. L., Piston, D. W., Baehr, W. & Palczewski, K. J Cell Biol 164, 373-383 (2004); Batten, M. L., et al. PLoS medicine 2, e333 (2005); Redmond, T. M., et al. Nat Genet 20, 344-351 (1998); Van Hooser, J. P., et al. Proceedings of the National Academy of Sciences of the United States of America 97, 8623-8628 (2000); Van Hooser, J. P., et al. J Biol Chem 277, 19173-19182 (2002)).
The biochemical defects causing LCA-like symptoms in Lrat−/− and Rpe65−/− knockout mice can be bypassed by oral gavage with 9-cis-retinal. This treatment results in preserved retinal morphology and recovery of normal rod function as assessed by single cell recordings and ERG measurements (Batten, M. L., et al. PLoS medicine 2, e333 (2005); Van Hooser, J. P., et al. Proceedings of the National Academy of Sciences of the United States of America 97, 8623-8628 (2000); Van Hooser, J. P., et al. J Biol Chem 277, 19173-19182 (2002)). 9-cis-retinal forms photoactive isorhodopsin which, when bleached, undergoes conformational changes via the same photoproducts as does rhodopsin naturally regenerated from 11-cis-retinal (Yoshizawa, T. & Wald, G. Nature 214, 566-571 (1967)). In addition, 11-cis-retinal given by intraperitoneal injection also improves vision in Rpe65−/− mice (Ablonczy, Z., et al. J Biol Chem 277, 40491-40498 (2002)). Further, gastric gavage with a more chemically stable compound than either 9-cis- or 11-cis-retinal, i.e. 9-cis-retinyl acetate (9-cis-R-Ac), produces the same beneficial effects as 9-cis-retinal in Lrat−/− mice (Batten, M. L., et al. PLoS medicine 2, e333 (2005)). Other synthetic retinal derivatives that can be used to restore and/or stabilize photoreceptor function have been described, for example, in WO 2006/002097 A2.
Currently, there are few treatments for retinoid deficiency. One treatment, a combination of antioxidant vitamins and zinc, produces only a small restorative effect by slowing the progression of AMD. Thus, there is a need for methods of restoring or stabilizing photoreceptor function in aging subjects. The present invention is related to the surprising discovery that long-term treatment with a synthetic retinoid derivative significantly improves age-related deterioration of photoreceptor function.